MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2Zhou, Yang, Liu
et alBiochim Biophys Acta Mol Basis Dis (2025) 1871 (5), 167798
Abstract: To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed.Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.Copyright © 2025 Elsevier B.V. All rights reserved.
Gen inhibiting the Wnt/Ca2+ signaling pathway alleviates cerebral ischemia/reperfusion injuryLi, Liu, Wang
et alSci Rep (2025) 15 (1), 4661
Abstract: Cerebral ischemia/reperfusion injury (CIRI) is a major complication of acute ischemic stroke (AIS), characterized by calcium overload, oxidative stress, and cell apoptosis. In this study, we investigated the therapeutic potential of Genistein (Gen) in alleviating CIRI by focusing on its effects on the Wnt/Ca2+ signaling pathway. Using a rat model of cerebral ischemia/reperfusion and in vitro experiments on PC12 cells, we observed that Gen treatment reduced infarct size, improved neurological function, and mitigated calcium overload, oxidative stress, and apoptosis. Further analysis revealed that Gen regulates key proteins in the Wnt/Ca2+ signaling pathway, including Wnt5a and Frizzled-2, effectively preventing intracellular calcium accumulation and subsequent damage. The knockdown of Frizzled-2 confirmed the pathway's role in mediating calcium overload and subsequent damage. Our findings suggest that Gen alleviates CIRI by inhibiting the Wnt/Ca2+ signaling pathway, positioning it as a promising candidate for therapeutic intervention in stroke treatment.© 2025. The Author(s).
Investigating the role of Wnt3a and Wnt5a as critical factors of hepatic stellate cell activation in acute toxicant-induced liver injuryRutt, Orlicky, McCullough
Cell Biol Toxicol (2024) 41 (1), 5
Abstract: Toxicant exposure can lead to acute liver injury, characterized by hepatic reprogramming and wound healing. Hepatic stellate cells (HSC) play a key role in liver regeneration during wound healing by secreting fibrogenic factors and production of extracellular matrix (ECM). However, repetitive injury to the liver can lead to extensive scarring and liver fibrosis, indicating HSCs coordinate both regeneration and disease. Because the factors contributing to HSC reprogramming during wound healing are not fully defined, we sought to further characterize morphogenic pathways of regeneration in an acute model of toxicant-induced liver injury1. Wnt/β-catenin signaling has been recently associated with progressive liver fibrosis, but its role in HSC reprogramming is not well defined. Here, we investigated the canonical role of Wnt3a/Wnt5a on β-catenin-dependent HSC transdifferentiation and find that hepatic ECM gene expression is increased and associated with Wnt3a, Wnt5a, and their transducers (Frizzled-2 and Frizzled-7) after an acute exposure of the hepatotoxin, carbon tetrachloride(CCl4). Moreover, we find exogenous Wnt3a and Wnt5a can accelerate spontaneous, culture-induced HSC activation in vitro as evidenced by increased total expression of fibrogenic factors, including Col1a1 and α-SMA. Challenge with Wnt3a induced canonical β-catenin-dependent transcription of axin2, which was attenuated by the Wnt coreceptor antagonist, Dickkopf-1 (DKK-1). These data support a role for canonical Wnt signaling as an additional mechanism by which HSCs dynamically respond to liver injury during the early wound healing response. New & noteworthy. This study elucidates novel mechanisms of fibrotic gene reprogramming in the liver. Specifically, we describe that Wnts and their transducers are increased during early liver injury which are associated with early fibrogenic responses and for the first time, causally link Wnts as direct inducers of HSC activation in the liver.© 2024. The Author(s).
Wnt/Ca2+ pathway inhibits neural differentiation of human dental pulp stem cells in vitroWang, Wang, Luan
et alJ Dent Sci (2024) 19 (4), 2090-2099
Abstract: Dental pulp stem cells (DPSCs) have demonstrated significant potential for neuroregeneration. However, a full understanding of the specific mechanism underpinning the neural differentiation of DPSCs is still required. The Wnt signaling is crucial for the development of the embryonic neural system and the maintenance of adult neural homeostasis. This study aimed to investigate the role of the Wnt/Ca2+ pathway in the neural differentiation of human DPSCs (hDPSCs) and its modulation of the Wnt/β-catenin pathway.hDPSCs were cultured and divided into the control group and the neurogenic induction group (Neuro group). The mRNA and protein levels of neurogenic markers, Wnt/Ca2+, and Wnt/β-catenin pathway indicators were determined using Quantitative real-time PCR and Western blotting. After inhibition of the Wnt/Ca2+ pathway using a WNT5A short hairpin RNA (shRNA) plasmid and subsequent neurogenic induction, neurogenic markers and Wnt/β-catenin pathway indicators in the NC-sh-Neuro group and WNT5A-sh-Neuro group were determined using Quantitative real-time PCR and Western blotting.Compared with the control group, the expression of the Wnt/Ca2+ pathway indicators (WNT5A, Frizzled 2, calmodulin-dependent protein kinase IIa, and nuclear factor of active T cells 1) decreased in the Neuro group. Conversely, the expression of WNT3A, total β-catenin and active β-catenin in the Wnt/β-catenin pathway increased. Moreover, compared with the NC-sh-Neuro group, the WNT5A-sh-Neuro group exhibited a greater level of mature neural differentiation alongside elevated expression of the Wnt/β-catenin pathway indicators.The Wnt/Ca2+ pathway inhibited neural differentiation of hDPSCs and has a negative effect on the Wnt/β-catenin pathway in vitro.© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.
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